Department of Pharmaceutics, University of Florida, Gainesville, FL 32610, USA.
J Transl Med. 2011 Feb 24;9:21. doi: 10.1186/1479-5876-9-21.
Alpha-1 antitrypsin (AAT) is a multi-functional protein that has anti-inflammatory and tissue protective properties. We previously reported that human AAT (hAAT) gene therapy prevented autoimmune diabetes in non-obese diabetic (NOD) mice and suppressed arthritis development in combination with doxycycline in mice. In the present study we investigated the feasibility of hAAT monotherapy for the treatment of chronic arthritis in collagen-induced arthritis (CIA), a mouse model of rheumatoid arthritis (RA).
DBA/1 mice were immunized with bovine type II collagen (bCII) to induce arthritis. These mice were pretreated either with hAAT protein or with recombinant adeno-associated virus vector expressing hAAT (rAAV-hAAT). Control groups received saline injections. Arthritis development was evaluated by prevalence of arthritis and arthritic index. Serum levels of B-cell activating factor of the TNF-α family (BAFF), antibodies against both bovine (bCII) and mouse collagen II (mCII) were tested by ELISA.
Human AAT protein therapy as well as recombinant adeno-associated virus (rAAV8)-mediated hAAT gene therapy significantly delayed onset and ameliorated disease development of arthritis in CIA mouse model. Importantly, hAAT therapies significantly reduced serum levels of BAFF and autoantibodies against bCII and mCII, suggesting that the effects are mediated via B-cells, at least partially.
These results present a new drug for arthritis therapy. Human AAT protein and gene therapies are able to ameliorate and delay arthritis development and reduce autoimmunity, indicating promising potential of these therapies as a new treatment strategy for RA.
α-1 抗胰蛋白酶（AAT）是一种多功能蛋白，具有抗炎和组织保护特性。我们之前的研究报告表明，人 AAT（hAAT）基因治疗可预防非肥胖型糖尿病（NOD）小鼠的自身免疫性糖尿病，并与强力霉素联合抑制关节炎的发展。在本研究中，我们研究了 hAAT 单药治疗在胶原诱导性关节炎（CIA）中治疗慢性关节炎的可行性，CIA 是一种类风湿关节炎（RA）的小鼠模型。
DBA/1 小鼠用牛型 II 胶原（bCII）免疫以诱导关节炎。这些小鼠用 hAAT 蛋白或表达 hAAT 的重组腺相关病毒载体（rAAV-hAAT）预处理。对照组接受生理盐水注射。通过关节炎的发生率和关节炎指数评估关节炎的发展。通过 ELISA 测试 B 细胞激活因子 TNF-α 家族（BAFF）和针对牛型（bCII）和鼠型胶原 II（mCII）的抗体的血清水平。
hAAT 蛋白治疗和重组腺相关病毒（rAAV8）介导的 hAAT 基因治疗均显著延迟 CIA 小鼠模型中关节炎的发病并改善疾病的发展。重要的是，hAAT 治疗显著降低了 BAFF 和针对 bCII 和 mCII 的自身抗体的血清水平，这表明作用至少部分通过 B 细胞介导。
这些结果为关节炎治疗提供了一种新的药物。人 AAT 蛋白和基因治疗能够改善和延迟关节炎的发展并减少自身免疫，表明这些治疗方法作为 RA 的一种新的治疗策略具有很大的潜力。
